3952 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Romanelli et al.
was collected, anhydrified, and evaporated. The residue was
purified by flash chromatography using CHCl3/MeOH 95:5 as
eluent, giving the title compound in 40% yield. [1H]-NMR
(CDCl3, δ): 2.35 (s, 3H, CH3); 2.37 (s, 3H, NCH3); 2.56-2.63
(m, 4H) and 3.19-3.26 (m, 4H) (piperazine protons); 6.65-
6.81 (m, 3H), and 7.12-7.26 (m, 1H) (aromatic protons) ppm.
[13C]-NMR (CDCl3, δ): 22.28 (q), 46.57 (t), 49.56 (t), 55.61 (t),
113.62 (d), 117.26 (d), 121.00 (d), 129.32 (d), 139.02 (s), 151.70
(s) ppm. The oxalate salt melted at 105-110 °C.
1-(3′-Hyd r oxyp h en yl)-4-m eth ylp ip er a zin e (11b). 1-(3′-
Methoxyphenyl)-4-methylpiperazine 12b (0.45 g, 2.18 mmol)
in 4 mL of HBr 40% were kept at 100 °C for 60 h. After cooling
at 0 °C, the mixture is basified to pH 8 with NaOH and
extracted with CHCl3. After anhydrification (Na2SO4) and
removal of solvent, the residue was purified by column
chromatography (CHCl3/CH3OH 90/10 as eluent) to obtain the
title compound (0.37 g, 88% yield). [1H]-NMR (CDCl3, δ): 2.36
(s, 3H, NCH3); 2.56-2.65 (m, 4H) and 3.10-3.20 (m, 4H)
(piperazine protons); 6.25-6.38 (m, 2H, aromatics); 6.46 (d,
1H, J ) 8.0 Hz), 6.62 (bs, 1H, OH); 7.08 (d, 1H, J ) 8 Hz)
(aromatic protons) ppm. [13C]-NMR (CDCl3, δ): 46.10 (q), 48.90
(t), 55.11 (t), 104.19 (d), 107.92 (d), 108.47 (d), 130.30 (d),
152.68 (s), 158.00 (s) ppm. Anal. C11H16N2O (C,H,N). The
oxalate salt melted at 230 °C (after recrystallization from
absolute ethanol).
(d), 139.41 (s), 152.01 (s), 169.34 (s) ppm. Anal. C13H19N3O
(C,H,N). The oxalate salt melted at 150 °C.
1-(3′,4′-Meth ylen ed ioxyp h en yl)p ip er a zin e (25a ). Fol-
lowing the same procedure used for 7b, starting from (3,4-
methylenedioxy)aniline (2 g, 0.0146 mol), bis(2-chloroethyl)-
amine hydrochloride (2.6 g, 0.0146 mol), and Na2CO3 (3.09 g,
0.0292 mol), the title compound was obtained in 35% yield
after purification by flash chromatography using CHCl3/MeOH
85:15 as eluent. [1H]-NMR (CDCl3, δ): 1.90 (bs, 1H, NH); 3.05
(s, 8H, piperazine protons); 5.92 (s, 2H, OCH2O); 6.37 (d, 1H,
J ) 9.2 and 3.1 Hz, H-6′), 6.57 (d, 1H, J ) 3.1 Hz, H-2′) and
6.73 (d, 1H, J ) 9.2 Hz) (aromatic protons). Compound 25a
was transformed into the oxalate salt by treatment with 1
equiv of oxalic acid in ethyl acetate: mp 253-258 °C.
1-(3′,4′-Methylenedioxyphenyl)-4-methylpiperazine (25b).
A solution of 25a (0.27 g, 1.3 mmol) and CH3I (80 µL, 1 equiv)
in diethyl ether was kept under stirring at room temperature
for 40 h. The solvent was evaporated under vacuum, and the
residue was treated with NaHCO3 and extracted with CHCl3.
After anhydrification (Na2SO4) and removal of solvent, the
residue was purified by column chromatography (CHCl3/CH3-
OH 85/15 as eluent) to obtain 0.1 g of the desired compound
(25% yield). [1H]-NMR (CDCl3, δ): 2.38 (s, 3H, NCH3); 2.55-
2.65 (m, 4H) and 3.04-3.13 (m, 4H) (piperazine protons); 5.91
(s, 2H, OCH2O); 6.48 (dd, 1H, J ) 9.6 and 3.2 Hz, H-6′), 6.56
(m, 1H, H-2′) and 6.72 (dd, 1H, J ) 9.6 and 1.9 Hz) (aromatic
protons) ppm. [13C]-NMR (CDCl3, δ): 46.37 (q), 51.04 (t), 55.53
(t), 100.29 (d), 101.20 (t), 108.50 (d), 109.36 (d), 141.88 (s),
147.58 (s), 148.51 (s) ppm. Anal. C12H16N2O2 (C,H,N). The
oxalate salt melted at 125 °C.
3-(4′-Met h ylp ip er a zin yl)cycloh ex-2-en -1-on e (26b ). A
mixture of 1,3-cyclohexanedione (0.3 g, 2.7 mmol) and N-
methylpiperazine (0.27 g, 2.7 mmol) in toluene (5 mL) was kept
under reflux for 4 h, with a Dean-Stark trap. After removal
of solvent, the residue was purified by column chromatography
(CHCl3/petroleum ether/absolute EtOH/NH4OH 1200/180/450/
9.9 as eluent). The title compound (0.3 g, 85% yield) was
obtained as a white, low-melting solid. [1H]-NMR (CDCl3, δ):
1.95-2.05 (m, 4H); 2.30 (s, 3H, NCH3); 2.25-2.35 (m, 2H, CH2-
CO); 2.40-2.50 (m, 4H) and 3.30-3.40 (m, 4H) (piperazine
protons); 5.30 (s, 1H, CdCH) ppm. [13C]-NMR (CDCl3, δ):
22.42 (t), 27.24 (t), 35.90 (t), 46.19 (q), 46.20 (t), 54.71 (t),
100.27 (d), 165.19 (s), 197.62 (s) ppm. Anal. C11H18N2O (C,H,N).
The oxalate salt, after crystallization from absolute ethanol,
melted at 143 °C.
3-(4′-Meth ylpiper azin yl)cyclopen t-2-en -1-on e (27b). Fol-
lowing the same procedure as for 26b, starting from 0.4 g (4
mmol) of 1,3-cyclopentanedione and 0.4 g (4 mmol) of N-
methylpiperazine, the desired product (0.5 g, 70% yield) was
obtained. [1H]-NMR (CDCl3, δ): 2.30 (s, 3H, NCH3); 2.35-2.45
(m, 6H); 2.55-2.65 (m, 2H, CH2CO); 3.30-3.45 (m, 4H,
piperazine protons); 5.05 (s, 1H, CdCHCO) ppm. [13C]-NMR
(CDCl3, δ): 27.60 (t), 34.25 (t), 46.34 (q), 47.57 (t), 54.62 (t),
100.73 (d), 176.68 (s), 204.03 (s) ppm. Anal. C10H16N2O (C,H,N).
The oxalate salt, after recrystallization from absolute ethanol,
melted at 172 °C.
1-(3′-Acet oxyp h en yl)-4-m et h ylp ip er a zin e (13b). 1-(3′-
Hydroxyphenyl)-4-methylpiperazine 11b (0.20 g, 1.04 mmol)
in CHCl3 (1 mL) and acetic anhydride (1 mL) were kept at 60
°C for 4 h. After removal of solvent, the residue was treated
with a saturated solution of NaHCO3 and extracted with
CHCl3. After anhydrification (Na2SO4) and removal of solvent,
the residue was purified by column chromatography (CHCl3/
petroleum ether/absolute EtOH/ NH4OH 1200/180/450/9.9 as
eluent); 0.21 g of the desired compound were obtained (86%
yield). [1H]-NMR (CDCl3, δ): 2.27 (s, 3H, COCH3); 2.34 (s, 3H,
NCH3); 2.47-2.55 (m, 4H) and 3.18-3.25 (m, 4H) (piperazine
protons); 6.52-6.61 (m, 2H), 6.77 (d, 1H, J ) 9 Hz) and 7.23
(dd, 1H, J ) 9 Hz) (aromatic protons) ppm. [13C]-NMR (CDCl3,
δ): 21.61 (q), 46.52 (t), 49.01 (t), 55.35 (t), 109.25 (d), 112.60
(d), 113.49 (d), 130.01 (d), 151.95 (s), 152.68 (s), 169.81 (s) ppm.
Anal. C13H18N2O2 (C,H,N). The oxalate salt melted at 95 °C.
1-(3′-Am in op h en yl)-4-m eth ylp ip er a zin e (14b).35 A mix-
ture of 17b (0.5 g, 2.26 mmol), SnCl2‚2H2O (3.1 g, 14 mmol),
and concentrated HCl (4.3 mL) was stirred at room temper-
ature for 24 h, then it was made alkaline with NaOH, and
extracted with chloroform. After anhydrification (Na2SO4) and
removal of solvent, the residue was purified by flash chroma-
tography (CHCl3/petroleum ether/absolute EtOH/NH4OH 340/
60/65/8 as eluent). The title compound was obtained in 58%
yield. [1H]-NMR (CDCl3, δ): 2.39 (s, 3H, NCH3); 2.55-2.68 (m,
4H) and 3.18-3.27 (m, 4H) (piperazine protons); 3.65 (bs, 2H,
NH2); 6.20-6.30 (m, 2H), 6.35 (dd, 1H, J ) 8 and 2.5 Hz, 6′-
H), and 7.06 (dd, 1H, J ) 8 Hz, 5′-H) (aromatic protons) ppm.
4-(3′-Am in op h en yl)-1,1-d im et h ylp ip er a zin iu m Br o-
m id e Hyd r obr om id e (14c). A mixture of 39c (0.2 g, 0.54
mmol) in a 33% acetic acid solution of HBr (3 mL) was kept
at room temperature for 12 h, then the solvent was evaporated,
and the residue was recrystallized twice from absolute ethanol.
Mp 240 °C. [1H]-NMR (D2O, δ): 3.15 (s, 6H, N(CH3)2); 3.41-
3.55 (m, 8H, piperazine protons); 6.43-6.51 (m, 2H), 6.58 (d,
1H, J ) 8.4 Hz) and 7.18 (dd, 1H, J ) 8.4 and 7.8 Hz, 5′-H)
(aromatic protons) ppm. Anal. C12H20BrN3‚HBr‚H2O: % calc
C 37.47, H 6.02, N 10.91; found C 37.62, H 6.03, N 11.60.
1-(3′-P yr id a zin yl)p ip er a zin e (29a ). A mixture of 3,6-
dichloropyridazine (0.7 g, 5 mmol) and 1-benzylpiperazine (0.9
g, 5 mmol) was kept at 90 °C for 4 h. After cooling, the mixture
was extracted with CHCl3, the solution was dried (Na2SO4),
and the solvent was removed under vacuum. The residue,
1-(6′-ch lor o-3′-p yr id a zin yl)-4-ben zylp ip er a zin e (40), was
obtained in 74% yield and was used in the next step without
further purification. [1H]-NMR (CDCl3, δ): 2.60 (t, 4H, J ) 4
Hz, piperazine protons); 3.60 (s, 2H, N-CH2-Ph); 3.63 (t, 4H,
1-(3′-Acetylam in oph en yl)-4-m eth ylpiper azin e (15b). Fol-
lowing the same procedure as for 13b, starting from 14b (0.24
g, 1.25 mmol), CHCl3 (1 mL), and acetic anhydride (2 mL),
0.15 g of the desired compound was obtained (51% yield). [1H]-
NMR (CDCl3, δ): 2.11 (s, 3H, COCH3); 2.32 (s, 3H, NCH3);
2.51-2.58 (m, 4H) and 3.15-3.24 (m, 4H) (piperazine protons);
6.65 (d, 1H, J ) 9.5 Hz), 6.85 (d, 1H, J ) 10 Hz), 7.15 (dd, 1H,
J ) 10 and 9.5 Hz) and 7.27 (s, 1H) (aromatic protons); 7.68
(s, 1H, NH) ppm. [13C]-NMR (CDCl3, δ): 24.94 (q), 46.50 (q),
49.16 (t), 55.39 (t), 108.09 (d), 111.56 (d), 112.09 (d), 129.68
J
) 4 Hz, piperazine protons); 6.87 (d, 1H, J ) 10 Hz,
pyridazine); 7.18 (d, 1H, J ) 10 Hz, pyridazine); 7.33-7.50
(m, 5H, aromatic protons). This compound (1.0 g) was dissolved
in methanol (10 mL), Pd/C (0.25 g) and ammonium formate
(0.6 g) were added, and the mixture was kept under reflux for
12 h. The solvent was removed under vacuum, and the residue
was dissolved in a saturated solution of NaHCO3 and extracted
with CHCl3. After anhydrification (Na2SO4) and removal of
solvent, the residue was purified by column chromatography